This invention relates to a method of treatment of androgen-related diseases such as prostate cancer in warm-blooded male animals (including humans) in need of such treatment, and in particular, to a combination therapy comprising administering an antiandrogen in association with an inhibitor of sex steroid biosynthesis to such animals. The invention also includes pharmaceutical compositions and kits useful for such treatment. Androgen-dependent diseases include diseases whose onset, maintenance or progress is, at least in part, dependent upon biological activities induced by androgens (e.g. testosterone and dihydrotestosterone). In one embodiment, the invention provides a treatment of hormone-dependent prostate cancer in warm-blooded male animals which comprises administering both an antiandrogen and at least one inhibitor of sex steroid biosynthesis capable of inhibiting conversion of dehydroepiandrosterone or 4-androstenedione to natural sex steroids in extra-testicular and extra-adrenal tissues.
While various investigators have been studying hormone-dependent prostate cancer, none have proposed the combination therapy of this invention.
A. V. Schally et al., Cancer Treatment Reports, 68 (No. 1) 281-289 (1984), summarize the results of animal and clinical studies on growth inhibition of hormone-dependent mammary and prostate tumors by use of analogues of luteinizing hormone-releasing hormones, the so-called LHRH agonists and suggest that LHRH analogs and/or antagonists may have potential for treating breast cancer.
T. W. Redding and A. V. Schally, Proc. Natl Acad. Sci. UA 80, 1459-1462 (1983), relates to inhibition of prostate tumor growth in rats by chronic use of an LHRH agonist, [D-Trp.sup.6 ]LHRH.
U.S. Pat. No. 4,329,364 relates to use of the antiandrogen, 4'-nitro-3'trifluoromethyl isobutyranilide for treatment of prostatic cancer.
U.S. Pat. No. 4,472,382 relates to treatment of prostate adenocarcinoma, benign prostate hypertrophy and hormone-dependent mammary tumors may with various LHRH agonists and treatment of prostate adenocarcinoma and benign hypertrophy by use of various LHRH agonists and an antiandrogen.
U.S. Pat. No. 4,659,695 (Labrie) relates to treatment of prostate cancer in animals whose testicular hormonal secretions are blocked. The method of treatment includes administering an antiandrogen such as flutamide as an inhibitor of sex steroid biosynthesis such as aminoglutethimide and/or ketoconazole.
Some clinical improvement in men with prostate cancer by use of the two LHRH agonists, Buserelin and Leuprolide, is also reported by N. Faure et al. at pages 337-350 and by R. J. Santen et al. at pages 351-364, respectively, LHRH and its Analogues--A new Class of Contraceptive and therapeutic Agents (B. H. Vickery and J. J. Nestor, Jr., and E. S. E. Hafez, eds), Lancaster, MTP Press, (1984).
R. Santen et al., he Journal of Steroid Biochemistry, volume 20, no 6B, at page 1375 (1984), relates that the use of ketoconazole in combination with chronic administration of Leuprolide in rodents decreased basal and Leuprolide-stimulated testosterone levels.
One of Applicant's Co-pending U.S. patent applications Ser. No. 07/321,926 filed Mar. 10, 1989, now abandoned, relates to a combination therapy for treatment of estrogen-related diseases by inhibiting ovarian hormonal secretions and administering an antiestrogen in combination with at least one of several enumerated activity blockers, sex steroid formation inhibitors and the like.
D. Kerle et al., The Journal of Steroid Biochemistry, volume 20, no. 6B, at page 1395 (1984) relates to the combined use of a LHRH analogue and ketoconazole producing objective responses in some prostate cancer patients who have relapsed or failed to respond to treatment with a LHRH analogue alone.
F. Labrie et al., The Prostate, 4, 579-594 (1983), disclose that use of a combination therapy of an LHRH agonist (Buserelin) and an antiandrogen (Anandron) to treat advanced prostate cancer in previously untreated patients effects simultaneous elimination of androgens of both testicular and adrenal origin.
F. Labrie et al., J. Steroid Biochem., 19, 999-1007 (1983), disclose the treatment of prostate cancer by the combined administration of an LHRH agonist and an antiandrogen. Labrie et al. disclose animal and clinical data in support of the proposition that the combined LHRH/antiandrogen treatment neutralizes the stimulatory influence of all androgens on the development and growth of androgen-dependent prostatic cancer.
F. Labrie et al., Abstracts of the 7th International Congress of Endocrinology, Excerpta Medica (1984) at page 98 disclose that treatment of prostate cancer patients with LHRH agonists alone causes a transient increase in serum androgen levels lasting for 5 to 15 days before castration levels are reached. While F. Labrie et al. recommend that orchiectomy, estrogen and LHRH agonists alone should not be further used for treatment of prostate cancer in the absence of a pure antiandrogen, there still is a need for a method of treatment of prostate cancer that effects more complete androgen blockage at the start as well as during the full period of treatment.
There are many data indicating that estrogens have a stimulatory effect on prostatic growth (Lee et al., 1981; J. Androl. 2: 293-299; Belis et al., 1983; J. Androl. 4: 144-149; Walsh and Wilson, 1976; J. Clin. Invest. 57: 1093-1097; De Klerk et al., 1985; Prostate 7, 1-12; Habesucht et al., 1987; Prostate 11: 313-326). Estrogens have also been found to enhance the growth-promoting effect of androgens (Farnsworth, 1969; Invest. Urol. 6: 423-427; Groom et al., 1971; Biochem. J. 122: 125-126; Lee et al., 1973; Steroids 22: 677-683).
Estrogen receptors have been demonstrated in human normal, hyperplastic and cancer prostatic tissue (Hobbs et al., 1989; Proc. 84th Endocrine Soc., Meeting, abst. No. 1410; Hobbs et al., 1983; J. Steroid Biochem. 19, 1279-1290; Wagner et al., 1975; Acta Endocrinol. (Kbh), suppl. 193, 52; and also in laboratory animal prostatic tissue (Swaneck et al., 1982; Biochem. Biophys. Res. Commun. 106: 1441-1447).
Moreover, androgen receptor levels were found to be elevated in prostatic tissue of patients treated with estrogen, thus indicating a stimulatory effect of estrogen on the level of androgen receptors in prostatic tissue (Hobbs et al., 1983; J. Ster. Biochem. 19, 1279-1290). A similar stimulatory effect of estrogen has been observed in the dog prostate (Moore et al., 1979; J. Clin. Invest. 63, 351-357).
In the prostate as well as in many other tissues, testosterone is irreversibly converted by 5.alpha.-reductase into the more potent androgen dihydrotestosterone (Bruchovsky and Wilson, J. Biol. Chem. 243: 2012-2021, 1968; Wilson, Handbook of Physiology 5 (section 7), pp. 491-508, 1975). inhibitors of 5.alpha.-reductase have been found to inhibit prostatic growth (Brooks et al., Endocrinology 109: 830, 1981; Brooks etal., Proc. Soc. Exp. Biol. Med. 169: 67, 1982 Brooks etal., Prostate 3: 35, 1982; Wenderoth etal., Endocrinology 113,569-573, 1983; McConnell et al., J. Urol. 141: 239A, 1989); Stoner, E., Lecture on the role of 5.alpha.-reductase inhibitor in benign prostatic hypertrophy, 84th AUA Annual Meeting, Dallas, May 8th, 1989.
The inhibitory effect of the 5.alpha.-reductase inhibitor Merck L. 652,931 on prostatic and seminal vesicle development in the prepubertal rat was described in Proc. 71st annual Meeting of Endocrine Society, abst. #1165, p. 314, 1989. The inhibitory effect of MK-906 on dihydrotestosterone formation in men has been described in men by Gormley et al., in Proc. 71st Annual Meeting of Endocrine Society, abst. #1225, p. 329, 1989 Imperato-McGinley et al., in Proc. 71st Annual Meeting of Endocrine Society, abst. #1639, p. 432, 1989; Geller and Franson, in Proc. 71st Annual Meeting of Endocr. Soc., abst. #1640, p. 432, 1989, and Tenover et al., in Proc. 71st Annual Meeting of Endocr. Soc., abst. #583, p. 169, 1989. The activity of the 5.alpha.-reductase inhibitors N,N-diethyl-4-methyl-3-oxo-4-aza-5.alpha.-androstane-17.beta.-carboxamide (4-MA) and 6-methylene-4-pregnene-3,20-dione (LY207320) has been described by Toomey et al., Proc. 71st Annual Meeting of Endocr. Sot., abst. #1226, p. 329, 1989.